Exploration of the Association between Cathepsin B and Parkinson’s Disease, and Integrative Analyses of Genome-Wide Association and Transcriptomics Data Linking Herpes Simplex Virus 1 Infection and Parkinson’s Disease

This thesis comprises two independent studies investigating two different aspects of Parkinson’s disease (PD)–related associations. Study 1: Exploration of the Association between Cathepsin B and PD Objective: This study aimed to examine the association between Cathepsin B and PD, placing specific focus on the potential mediating role of N-acetylaspartate. Methods: GWAS summary data were utilized to perform a two-sample Mendelian randomization (MR) analysis assessing the relationship between Cathepsin B (3,301 cases) and PD (4,681 cases). A sequential two-step MR analysis involving 8,148 cases was further conducted to evaluate the mediating effect of N-acetylaspartate. Results: The MR analysis indicated that genetically predicted higher Cathepsin B levels were associated with a lower risk of developing PD. Conversely, there was insufficient evidence to suggest that PD influenced Cathepsin B levels. The estimated mediating effect of N-acetylaspartate was 7.52%. Conclusion: The findings suggest that elevated Cathepsin B levels may reduce the risk of developing PD, potentially through a mediating effect of N-acetylaspartate. Further investigations are warranted to clarify the underlying mechanisms of this relationship. The main findings of this study have been published as a first-author paper in Brain Sciences (Lu et al., 2024). Study 2: Integrative Analyses Linking Herpes Simplex Virus 1 Infection and PD Objective: The main goal of this study is to explore the link between Herpes Simplex Virus 1 (HSV-1) infection, and PD from the Genome-Wide Association Studies (GWAS) data, and find the shared molecular signature for mechanism understanding and drug-repurposing from the transcriptomics data. Methods: We used summary-level GWAS data for causal inference, exploring the association between herpes keratitis (mainly caused by HSV-1) and PD. And used transcriptomics data to study the shared molecular signature for mechanism understanding and drug-repurposing. Results: The causal inference analysis implied that HSV-1 infection is related to PD. The up-regulated shared geneset between HSV-1 infection and PD is mainly enriched in neuroinflammation. While the down-regulated shared geneset is mainly enriched in stem cell and cellular metabolism. And the drug-repurposing targeted the shared molecular signature is Nalfurafine. Conclusion: HSV-1 infection is related to PD. And these two diseases had shared molecular signature such as neuroinflammation and stem cell, which could be targeted for drug-repurposing. This work has been submitted to Parkinson’s Disease.